Intranasal delivery of a nanoencapsulated ursodeoxycholic acid-ferulic acid prodrug enables CNS exposure to antioxidant agents

Ursodeoxycholic acid (UDCA) and ferulic acid (Fer) are recognized for their neuroprotective effects against oxidative stress, being antioxidant agents able to preserve cell mitochondrial functions. This makes them potentially useful for neuronal protection against neurodegenerative disorders. Consequently, a new prodrug (UDC-Fer-Me) was developed as an ester-conjugate of the methyl-derivative of ferulic acid (Fer-Me), which retains the antioxidant properties of Fer and UDCA. The prodrug was encapsulated in compritol-based solid lipid nanoparticles (SLNs) for its nasal administration and nose-to-brain delivery. HPLC measurements demonstrated that ( i ) UDC-Fer-Me is hydrolyzed in rat liver and brain homogenates, as well as following intravenous administration in rats, leading to the release of UDCA and Fer-Me; ( ii ) the prodrug is not detectable in the cerebrospinal fluid (CSF) after intravenous administration to rats; however, ( iii ) it permeates in vitro nasal mucosal cells, inducing its partial hydrolysis. UDC-Fer-Me also counteracted reactive oxygen species production induced by H2O2 on cultured neuronal cells. The UDC-Fer-Me-loaded SLNs showed a particle size distribution in the ∼0.1 μm order of magnitude and markedly improved the very slow dissolution rate of the prodrug in aqueous environments. Differential scanning calorimetry measurements suggested a good dispersion of the prodrug within the lipid matrix of SLNs; the drug loading was about 8% (61% entrapment efficiency). Following nasal administration of SLNs to rats (2 mg/kg dose), both the prodrug and Fer-Me were detected in the CSF at concentrations reaching up to 2 μg/mL, consistent with drug delivery to the central nervous system following intranasal administration.